Modeling drug-induced mitochondrial toxicity with human primary cardiomyocytes

Mitochondrial toxicity induced by therapeutic drugs is a major contributor for cardiotoxicity,posing a serious threat to pharmaceutical industries and patients’lives.However,mitochondrial toxicity testing is not incorporated into routine cardiac safety screening procedures.To accurately model native human cardiomyocytes,we comprehensively evaluated mitochondrial responses of adult human primary cardiomyocytes(h PCMs)to a nucleoside analog,remdesivir(RDV).Comparison of their response to human pluripotent stem cell-derived cardiomyocytes revealed that the latter utilized a mitophagy-based mitochondrial recovery response that was absent in h PCMs.Accordingly,action potential duration was elongated in h PCMs,reflecting clinical incidences of RDV-induced QT prolongation.In a screen for mitochondrial protectants,we identified mitochondrial ROS as a primary mediator of RDV-induced cardiotoxicity.Our study demonstrates the utility of h PCMs in the detection of clinically relevant cardiac toxicities,and offers a framework for h PCM-based high-throughput screening of cardioprotective agents.

Hepatotoxicity reports in the FDA adverse event reporting system database:A comparison of drugs that cause injury via mitochondrial or other mechanisms

Drug-induced liver injury(DILI) is a leading reason for preclinical safety attrition and postmarket drug withdrawals.Drug-induced mitochondrial toxicity has been shown to play an essential role in various forms of DILI,especially in idiosyncratic liver injury.This study examined liver injury reports submitted to the Food and Drug Administration(FDA) Adverse Event Reporting System(FAERS) for drugs associated with hepatotoxicity via mitochondrial mechanisms compared with non-mitochondrial mechanisms of toxicity.The frequency of hepatotoxicity was determined at a group level and individual drug level.A reporting odds ratio(ROR) was calculated as the measure of effect.Between the two DILI groups,reports for DILI involving mitochondrial mechanisms of toxicity had a 1.43(95% CI 1.42-1.45;P <0.0001) times higher odds compared to drugs associated with non-mitochondrial mechanisms of toxicity.Antineoplastic,antiviral,analgesic,antibiotic,and antimycobacterial drugs were the top five drug classes with the highest ROR values.Although the top 20 drugs with the highest ROR values included drugs with both mitochondrial and non-mitochondrial injury mechanisms,the top four drugs(ROR values> 18:benzbromarone,troglitazone,isoniazid,rifampin) were associated with mitochondrial mechanisms of toxicity.The major demographic influence for DILI risk was also examined.There was a higher mean patient age among reports for drugs that were associated with mitochondrial mechanisms of toxicity [56.1±18.33(SD)] compared to non-mitochondrial mechanisms [48±19.53(SD)](P <0.0001),suggesting that age may play a role in susceptibility to DILI via mitochondrial mechanisms of toxicity.Univariate logistic regression analysis showed that reports of liver injury were 2.2(odds ratio:2.2,95% CI 2.12-2.26) times more likely to be associated with older patient age,as compared with reports involving patients less than 65 years of age.Compared to males,female patients were 37% less likely(odds ratio:0.63,95% CI 0.61-0.64) to be subjects of liver injury reports for drugs associated with mitochondrial toxicity mechanisms.Given the higher proportion of severe liver injury reports among drugs associated with mitochondrial mechanisms of toxicity,it is essential to understand if a drug causes mitochondrial toxicity during preclinical drug development when drug design alternatives,more clinically relevant animal models,and better clinical biomarkers may provide a better translation of druginduced mitochondrial toxicity risk assessment from animals to humans.Our findings from this study align with mitochondrial mechanisms of toxicity being an important cause of DILI,and this should be further investigated in real-world studies with robust designs.

Mechanisms of Accelerated Liver Fibrosis Progression during HIV Infection

With the introduction of antiretroviral therapy (ART),a dramatic reduction in HIV-related morbidity and mortality has been observed.However,it is now becoming increasingly clear that liver-related complications,particularly rapid fibrosis development from ART as well as from the chronic HIV infection itself,are of serious concern to HIV patients.The pathophysiology of liver fibrosis in patients with HIV is a multifactorial process whereby persistent viral replication,and bacterial translocation lead to chronic immune activation and inflammation,which ART is unable to fully suppress,promoting production of fibrinogenic mediators and fibrosis.In addition,mitochondrial toxicity,triggered by both ART and HIV,contributes to intrahepatic damage,which is even more severe in patients co-infected with viral hepatitis.In recent years,new insights into the mechanisms of accelerated fibrosis and liver disease progression in HIV has been obtained,and these are detailed and discussed in this review.